1. Field of the Invention
This invention relates to a process for production of 2-amino-4-hydroxyquinolines and to intermediates therefor. More particularly, it relates to the reaction of an isatoic anhydride with malononitrile in the presence of a base to produce as intermediate a 2-amino-.alpha.,.alpha.-dicyanoacetophenone and a 2-amino-3-cyano-4-hydroxyquinoline, followed by hydrolysis and decarboxylation of said intermediates under acid or base conditions.
2. Description of the Prior Art
The synthesis of 2-amino-4-hydroxyquinolines via the fusion of ethyl cyanoacetate with anilinium benzenesulfonate or p-toluenesulfonate is described by Hardman et al., J. Chem. Soc., 3878 (1954). Gabriel, Ber., 51, 1500 (1918) reports preparation of 2-amino-4-hydroxyquinoline by reduction of ethyl .alpha.-cyano-.alpha.-(o-nitrobenzoyl)acetate and by hydrolysis of .alpha.-cyano-.alpha.-(o-phthalimidobenzoyl)acetate. These methods, however, are characterized by relatively low yields, poor availability of necessary reactants and, in the case of the fusion procedure described above, limitation as to the amount of product which can be made in a single preparation.
For convenience, isatoic anhydride, the trivial but widely used and recognized name for 2H-3,1-benzoxazine-2,4(1H)-dione, is used throughout this document.
The reaction of N-alkyl isatoic anhydrides with malonic acid esters to produce N-alkylquinolinediones is reported by Coppola, et al, J. Org. Chem., 41, 825 (1976). The replacement of malonic esters by compounds having an active methylene group and an electrophilic group capable of reacting with the liberated anilino nitrogen, for example, carbanions of the appropriate nitroacetate, phosphonoacetate, phosphonoacetonitrile or .beta.-ketosulfone, permits introduction of nitrogen, phosphorous or sulfur substituents in the 3-position of the quinoline system.
Coppola, et al, (loc. cit.), also describe the reaction of N-(3-chloropropyl)isatoic anhydride and of N-(2-propynyl)isatoic anhydride with the sodium salt of malononitrile to produce 2,3,4,6-tetrahydro-6-oxo-1H-pyrimido[1,2-a]quinoline-5-carbonitrile and 1,2,3,5-tetrahydro-2-methylene-5-oxoimidazo[1,2-a]quinoline-4-carbonitrile , respectively.